This application relates to antisense treatments for melanoma by inhibition of clusterin, also known as testosterone-repressed prostate message-2 (TRPM-2), for example by the administration of antisense oligonucleotides specific for clusterin.
Clusterin or TRPM-2 is a ubiquitous protein, with a diverse range of proposed activities. In prostate epithelial cells, expression of Clusterin increases immediately following castration, reaching peak levels in rat prostate cells at 3 to 4 days post castration, coincident with the onset of massive cell death. These results have led some researchers to the conclusion that clusterin is a marker for cell death, and a promoter of apoptosis. On the other hand, the observation that Sertoli cells and some epithelial cells express high levels of clusterin without increased levels of cell death, raises questions as to whether this conclusion is correct. Sensibar et al., Cancer Research 55: 2431-2437 (1995) reported on in vitro experiments performed to more clearly elucidate the role of clusterin in prostatic cell death. They utilized LNCaP cells transfected with a gene encoding clusterin and observed whether expression of this protein altered the effects of tumor necrosis factor α (TNFα), to which LNCaP cells are very sensitive, with cell death normally occurring within about 12 hours. Treatment of the transfected LNCaP cells with TNFα was shown to result in a transient increase in clusterin levels for a period of a few hours, but these levels had dissipated by the time DNA fragmentation preceding cell death was observed. Using an antisense molecule corresponding to the bases 1-21 of the clusterin sequence, but not other clusterin antisense oligonucleotides, resulted in a substantial reduction in expression of clusterin, and an increase in apoptotic cell death in LNCaP cells exposed to TNFα. This led Sensibar et al. to the hypothesis that overexpression of clusterin could protect cells from the cytotoxic effect of TNF, and that clusterin depletion is responsible for the onset of cell death, although the mechanism of action remains unclear.
PCT Publication WO00/049937, which is incorporated herein by reference in all jurisdictions permitting such incorporation, describes the use of antisense therapy which reduces the expression of clusterin to provide therapeutic benefits in the treatment of cancer of prostate cancer, renal cell cancer and some breast cancers. Furthermore, combined use of antisense clusterin plus cytotoxic chemotherapy (e.g. taxanes) synergistically enhances chemosensitivity in hormone refractory prostate cancer. Radiation sensitivity is also enhanced when cells expressing clusterin are treated with antisense clusterin oligodeoxynucleotides (ODN).